In recent years, a number of important differences between men and women have been identified in the regulation of the storage and metabolism of energy yielding substrates. Such differences have implications for sex-specific etiology and treatment of diseases, especially diseases that have a strong metabolic basis such as obesity, type 2 diabetes, and coronary heart disease. The PI has preliminary data showing that there is a reduced catecholamine response to exercise in women vs men and that this is associated with similar or greater increases in circulating glycerol and free-fatty acid (FFA) levels, but similar glucose levels. In addition, women have a higher relative contribution of lipid to total fuel oxidation during exercise compared to men. This suggests an increased sensitivity to the lipolytic action of catecholamines in women vs men and an increased propensity to utilize lipid when lipid is mobilized. This data was confirmed during matched, resting, infusions of epinephrine, norepinephrine, or the 2 combined in men and women. That is, women had higher glycerol levels vs men and a greater contribution of lipid to total fuel oxidation during each infusion. In addition, glucose concentrations were significantly greater in women vs men after epinephrine but not after norepinephrine or epinephrine plus norepinephrine. Studies in Specific Aim 1 of the current proposal will identify the specific adrenergic receptors (B and/or a) involved in these sex differences in systemic substrate changes and fuel oxidation. This will be achieved via resting infusions of specific adrenergic agonists, and/or antagonists, combined with stable isotope measures of glycerol, palmitate and glucose turnover and whole-body measures of respiratory gas exchange and palmitate oxidation. In order to begin to determine the role of the sex-steroids in the sex differences in catecholamine stimulated substrate metabolism, Specific Aim 2 will use a gonadotropin-releasing hormone (GnRH) antagonist to suppress endogenous sex-steroid production in men. Epinephrine stimulated substrate metabolism will be studied pre-GnRH treatment, in the suppressed state and then following testosterone add back. In this GnRH suppression study, metabolism will be assessed via stable isotope measures of glycerol, FFA and glucose turnover and whole-body respiratory gas exchange measures. [unreadable] [unreadable]